Mechanistic Assessment of the Effect of Omeprazole on the In Vivo Pharmacokinetics of Itraconazole in Healthy Volunteers

  • Ahmad Y. AbuhelwaEmail author
  • Stuart Mudge
  • Richard N. Upton
  • David J. R. Foster
Original Research Article


Background and Objective

SUBA-itraconazole and Sporanox are two oral formulations of itraconazole. Drug–drug interactions with omeprazole have been previously reported; however, mechanistic understanding of the pharmacological and physiological interactions of omeprazole with orally administered itraconazole within a population modeling paradigm is lacking. The objective of this analysis was to mechanistically describe and quantify the effect of omeprazole on the pharmacokinetics of itraconazole and its major metabolite, hydroxyitraconazole from the SUBA itraconazole and Sporanox formulations.


An in vitro–in vivo (IVIV) pharmacokinetic model of itraconazole and hydroxyitraconazole was developed including data from an omeprazole interaction study with SUBA itraconazole. Meta-models of gastric pH for healthy subjects and subjects receiving omeprazole were integrated into the IVIV model to capture omeprazole-mediated gastric pH changes on itraconazole dissolution and absorption.


Omeprazole influenced the kinetics of itraconazole through altering the dissolution and absorption due to the pH-dependent solubility of itraconazole, inhibition of efflux transporters, and inhibiting the metabolism of itraconazole and hydroxyitraconazole. The model-predicted population effects of omeprazole on itraconazole from SUBA-itraconazole were to increase the area under the concentration–time curve (AUC0–24) and maximum concentration (Cmax) by 35 and 31%, respectively, and to decrease AUC0–24 and Cmax from Sporanox by 68 and 76%, respectively.


Unlike SUBA itraconazole, which requires basic pH for itraconazole release, the omeprazole-induced pH-mediated reduction in Sporanox dissolution overrides any increased exposure from the drug–drug interaction at hepatic metabolizing enzymes or efflux transporters. The model presented here is the most complete quantitative description of the pharmacokinetics of itraconazole and hydroxyitraconazole currently available.



AYA is supported at the School of Pharmacy and Medical Sciences at the University of South Australia by a Science and Industry Endowment Fund STEM + Business Fellowship of the Commonwealth Scientific and Industrial Research Organisation. The Australian Centre for Pharmacometrics is an initiative of the Australian Government as part of the National Collaborative Research Infrastructure Strategy.

Compliance with Ethical Standards


All pharmacokinetic studies of Sporanox and SUBA-itraconazole used in the analysis were sponsored by Mayne Pharma International, Salisbury South, South Australia, Australia.

Conflict of Interest

SM is an employee at Mayne Pharma. DJRF, RNU and AYA have acted as paid consultants for Mayne Pharma International, Salisbury South, South Australia, Australia.

Ethical Approval

All oral pharmacokinetic studies were conducted by Mayne Pharma International, Salisbury South, South Australia, Australia, in accordance with the ICH Guidelines for Good Clinical Practice, the Declaration of Helsinki on the ethical conduct of medical research, and applicable regulatory requirements.

Informed Consent

Each subject provided written informed consent before study participation.

Supplementary material

13318_2018_519_MOESM1_ESM.pdf (467 kb)
Supplementary material 1 (PDF 467 kb)


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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Australian Centre for Pharmacometrics and Sansom Institute, School of Pharmacy and Medical SciencesUniversity of South AustraliaAdelaideAustralia
  2. 2.Mayne Pharma InternationalSalisbury SouthAustralia

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